Mannitol

From Wikipedia, the free encyclopedia

D-Mannitol

Systematic (IUPAC) name

(2R,3R,4R,5R)-Hexane-1,2,3,4,5,6-hexol

Identifiers

CAS number 69-65-8

ATC code A06AD16 B05BC01 B05CX04R05CB16

PubChem CID 6251

DrugBank APRD01083

ChemSpider 6015

ChEMBL CHEMBL689 

Chemical data

Formula C6H14O6 
 Mol. mass 182.172

SMILES eMolecules & PubChem

Pharmacokinetic data

Bioavailability ~7%

Metabolism Hepatic, negligible.

Half-life 100 minutes

Excretion Renal: 90%

Therapeutic considerations

Pregnancy cat. C: (USA)

Legal status  ?

Routes Intravenous

Oral

  (what is this?)  (verify)

Mannitol is a white, crystalline[1] organic compound with the formula (C6H8(OH)6). This polyol is used as

an osmotic diuretic agent and a weak renal vasodilator. It was originally isolated from the secretions of
the flowering ash, called manna after their resemblance to the Biblical food, and is also referred to
as mannite and manna sugar.[2] In plants, it is used to induce osmotic stress.

Contents
 [hide]

1 Chemistry

2 Obtaining mannitol

o 2.1 Industrial

synthesis
 o 2.2 Biological

syntheses

o 2.3 Natural product

extraction

3 Uses

o 3.1 Medical

applications

o 3.2 In foods

o 3.3 In illicit drugs

4 Controversy

5 Toxicology

6 Compendial status

7 See also

8 Notes and references

9 External links

[edit]Chemistry

Mannitol is a sugar alcohol; that is, it is derived from a sugar by reduction, with a molecular weight of 182.17
g/mol,[3] and a density of 1.52 g/mL.[4] Other sugar alcohols include xylitol andsorbitol. Mannitol and sorbitol are
isomers, the only difference being the orientation of the hydroxyl group on carbon 2. [5] Aqueous solutions of
mannitol are mildly acidic and sometimes such solutions are treated to lower the pH. Chemical Abstracts
Registry Numbers for mannitol are 123897-58-5, 69-65-8 (D-Mannitol), 75398-80-0, 85085-15-0, and 87-78-5
(mannitol with unspecified stereochemistry). D-Mannitol (CAS# 69-65-8) has a solubility of 22g mannitol/
100mL water (25°C), and a relative sweetness of 50 (sucrose=100).[3] It melts between 165°-169°C (7.6 torr),
and boils at 295°C at 3.5 torr, indicating a greater boiling point at STPconditions.[4]

[edit]Obtaining mannitol
[edit]Industrial synthesis
Mannitol is commonly formed via the hydrogenation of fructose, which is formed from either starch or sugar.
Although starch is cheaper than sucrose, the transformation of starch is much more complicated. Eventually, it
yields a syrup containing about 42% fructose, 52% dextrose, and 6% maltose. Sucrose is simply hydrolyzed
into an invert sugar syrup, which contains about 50% fructose. In both cases, the syrups are
chromatographically purified to contain 90-95% fructose. The fructose is then hydrogenated over a nickel
catalyst into mixture of isomers sorbitol and mannitol. Yield is typically 50%:50%, although
slightly alkaline reaction conditions can slightly increase mannitol yields.[5]

[edit]Biological syntheses
Mannitol is one of the most abundant energy and carbon storage molecules in nature, produced by a plethora
of organisms, including bacteria, yeasts, fungi, algae, lichens, and many plants. [6] Fermentation by
microorganisms is a possible alternative to traditional industrial synthesis, producing much higher yields of
mannitol, with minimal to no side products. A fructose to mannitol metabolic pathway, known as the mannitol
cycle in fungi, has been discovered in a type of red algae (Caloglossa leprieurii), and it is highly possible that
other microorganisms employ similar such pathways. [7] A class of lactic acid bacteria,labeled heterofermentive
because of their multiple fermentation pathways, convert either 3 fructose molecules or 2 fructose and 1
glucose molecule into 2 mannitol molecules, and one molecule each of lactic acid, acetic acid, and carbon
dioxide. Feedstock syrups containing medium to large concentrations of fructose (for example, cashew apple
juice, containing 55% fructose: 45% glucose) can produce yields 200g mannitol/ liter feedstock. Further
research is being conducted, studying ways to engineer even more efficient mannitol pathways in lactic acid
bacteria, and also studying the use of other microorganism, such as yeast[6] and e. coli bacteria in mannitol
productions. When food grade strains of any of the aforementioned microorganisms are used, the mannitol and
the organism itself are directly applicable to food products, avoiding the need for careful separation of
microorganism and mannitol crystals. Although this is a promising method,steps are needed to scale it up to
industrially needed quantities.[7]

[edit]Natural product extraction

As stated above, mannitol is found in a wide variety of natural products, including almost all plants. This allows
for direct extraction from natural products, rather than chemical or biological syntheses. In fact, in China,
isolation from seaweeds is the most common form of mannitol production. [1] Mannitol concentrations of
plant exudates can range from 20% in seaweeds to 90% in the plane tree. Traditionally, mannitol is extracted
by the Soxhlet extraction, utilizing ethanol, water, and methanol to steam and then hydrolyze the crude
material. The mannitol is then recrystallized from the extract, generally resulting in yields of about 18% of the
original natural product. Another up and coming method of extraction is by
using supercritical and subcritical fluids. These fluids are at such a stage that there is no difference between
the liquid and gas stages, and are therefore more diffusive than normal fluids. This is considered to make them
much more effective mass transfer agents than normal liquids. The super/sub critical fluid is pumped through
the natural product, and the mostly mannitol product is easily separated from the solvent and minute amount of
byproduct. Supercritical carbon dioxide extraction of olive leaves has been shown to require less solvent per
grams of leaf than a traditional extraction (141.7 g CO2 vs. 194.4 g ethanol/ 1 g olive leaf). Heated,
pressurized, subcritical water is even cheaper, and is shown to have dramatically greater results than
traditional extraction. It requires only 4.01 g water/ 1 g olive leaf, and gives a yield of 76.75% mannitol. Both
super- and sub-critical extractions are cheaper, faster, purer, and more environmentally friendly than the
traditional extraction. However, the high required operating temperatures and pressures are cause for
hesitancy in the industrial use of this technique.[7]

[edit]Uses

[edit]Medical applications
Mannitol is used clinically in osmotherapy to reduce acutely raised intracranial pressure until more definitive
treatment can be applied, e.g., after head trauma. It is also used to treat patients with oliguric renal failure. It is
administered intravenously, and is filtered by the glomeruli of the kidney, but is incapable of being resorbed
from the renal tubule, resulting in decreased water and Na+ reabsorption via its osmotic effect. Consequently,
mannitol increases water and Na+ excretion, thereby decreasing extracellular fluid volume.

Mannitol can also be used as a facilitating agent for the transportation of pharmaceuticals directly into the brain.
The arteries of the blood-brain barrier are much more selective than normal arteries. Normally, molecules can
diffuse into tissues through gaps between the endothelial cells of the blood vessels. However, what enters the
brain must be much more rigorously controlled. The endothelial cells of the blood-brain barrier are connected
by tight junctions, and simple diffusion through them is impossible. Rather, active transport is necessary,
requiring energy, and only transporting molecules that the arterial endothelial cells have receptor signals for.
Mannitol is capable of opening this barrier by temporarily shrinking the endothelial cells, simultaneously
stretching the tight junctions between them.[8] An intracarotid injection of high molarity mannitol (1.4-1.6M),
causes the contents of the artery to be hyperosmotic to the cell. Water leaves the cell and enters the artery in
order to recreate an osmotic equilibrium. This loss of water causes the cells to shrivel and shrink, stretching the
tight junctions between the cells.[9] The newly formed gap reaches its peak width five minutes after mannitol
injection, and stays widely open for thirty minutes. During this timespan, drugs injected into the artery can
easily diffuse though the gaps between cells directly into the brain. [10] This makes mannitol indispensable for
delivering various drugs directly to the brain (e.g., in the treatment of Alzheimer's disease, or in chemotherapy
for brain tumors.[11]

Mannitol is commonly used in the circuit prime of a heart lung machine during cardiopulmonary bypass. The
presence of mannitol preserves renal function during the times of low blood flow and pressure, while the patient
is on bypass. The solution prevents the swelling of endothelial cells in the kidney, which may have otherwise
reduced blood flow to this area and resulted in cell damage.

Mannitol is also being developed by an Australian pharmaceutical company as a treatment for cystic

fibrosis and bronchiectasis and as a diagnostic test for airway hyperresponsiveness. The mannitol is orally
inhaled as a dry powder through what is known as an osmohaler and osmotically draws water into the lungs to
thin the thick, sticky mucus characteristic of cystic fibrosis. This is intended to make it easier for the sufferer to
cough the mucus up during physiotherapy. The critical characteristic of the mannitol is its particle size
distribution.

Mannitol is also the first drug of choice for the treatment of acute glaucoma in veterinary medicine. It is
administered as a 20% solution IV. It dehydrates the vitreous humor and, thus, lowers the intraocular pressure.
However, it requires an intact blood-ocular barrier to work. [12]

Mannitol can also be used to temporarily encapsulate a sharp object (such as a helix on a lead for an artificial
pacemaker) while it is passed through the venous system. Because the mannitol dissolves readily in blood, the
sharp point will become exposed at its destination.

Mannitol may be administered in cases of severe Ciguatera poisoning. Severe ciguatoxin, or "tropical fish

poisoning" can produce stroke-like symptoms.

Mannitol is the primary ingredient of Mannitol Salt Agar, a bacterial growth medium, and is used in others.

In oral doses larger than 20 g, mannitol acts as an osmotic laxative, and is sometimes sold as a laxative for
children[citation needed].

[edit]In foods
Mannitol does not stimulate an increase in blood glucose, and is therefore used as a sweetener for people
with diabetes, and in chewing gums. It also has a low glycemic index, making it a low carb food. Although
mannitol has a higher heat of solution than most sugar alcohols, its comparatively low solubility reduces the
cooling effect usually found in mint candies and gums. However, when mannitol is completely dissolved in a
product, it induces a strong cooling effect. [5] Also, it has a very low hygroscopicity- it does not pick up water
from the air until the humidity level is 98%. This makes mannitol very useful as a coating for hard candies, dried
fruits, and chewing gums, and it is often included as an ingredient in candies and chewing gum. [13] The pleasant
taste and mouthfeel of mannitol also makes it a popular excipient for chewable tablets.[14]

[edit]In illicit drugs

Mannitol is sometimes used as an adulterant or cutting agent for heroin, methamphetamines or other illicit
drugs. In popular culture, when it is used in this manner, it is often referred to as baby laxative.[15]

[edit]Controversy

The three studies[16][17][18] that initially found that high-dose mannitol was effective in cases of severe head injury
have been the subject of a recent investigation.[19] Although several authors are listed with Dr. Julio Cruz, it is
unclear whether the authors had knowledge of how the patients were recruited. Further, the Federal University
of São Paulo, which Dr. Cruz gave as his affiliation, has never employed him. Currently, therefore,
the Cochrane review recommending high-dose mannitol[20] has been withdrawn pending re-evaluation, as there
is some evidence that mannitol may worsen cerebral edema.[21]

[edit]Toxicology

Mannitol is contraindicated in patients with anuria and congestive heart failure.[citation